1. Field
The present application relates to systems and methods for opening a tissue utilizing microbubbles.
2. Background Art
The exchange of molecules across the cerebral microvasculature is strictly regulated by a unique interface known as the blood-brain barrier (BBB). Its primary function is to strictly regulate the brain's environment in order to prevent toxins from entering the parenchyma and maintain molecular environments necessary for proper neuronal firing. The result is the effective exclusion of nearly all systemically administered compounds larger than 400 Da (Daltons) from the brain's extracellular space, rendering many neurologically potent compounds ineffective. So, potential therapeutic agents, such as inhibitors (˜1 kDa) and antibodies (30 to 300 kDa), will not reach their intended targets if administered systemically. Until a method to deliver such large agents in the brain at a critical dose is shown to be effective, advances in the treatment of central nervous system (CNS) disorders will remain impaired.
Focused ultrasound (FUS) applied after the systemic injection of ultrasound contrast agents (UCA) can open the BBB noninvasively. This method can concurrently deliver agents to the brain through the intact skull, locally (to a targeted volume), and transiently with the BBB closing within hours of its opening. In the past, assessment of safety has involved histological analysis to determine the presence of apoptosis, neuronal death, and erythrocyte extravasations, and magnetic resonance imaging (MRI) to determine the presence of hemorrhage, macroscopic structural changes, and the timeline of BBB closure. Comprehensive histological analyses of the damage within a few days of sonication has revealed that at specific acoustic parameters (i.e., frequency, pulse length, pulse repetition frequency, and duration) and pressures, BBB opening can occur without widespread hemorrhage or neuronal damage. Other concerns include the presence of small erythrocyte extravasations and the potential of delayed long-term effects that would not be visible in the mostly acute histological evaluations performed. However, the FUS-induced BBB opening results were reproduced in old APP/PS1 Alzheimer's mice where subsequent BBB closure was observed. There is a shortage of effective treatments of CNS diseases and, thereby, a pressing need for a brain drug delivery technique. In light of this need and the lack of clinical options, the safety levels of FUS-induced BBB opening are promising for human applications.
In terms of efficacy, FUS-induced BBB opening can increase the BBB's permeability to therapeutically-relevant-sized agents, such as Omniscan™ (573 Da), Magnevist® (938 Da), Evans Blue, Trypan Blue, Herceptin (148 kDa), doxorubicin (544 Da), and rabbit anti-Aβ antibodies. However, the magnitude of this permeability increase, the spatial distribution of the trans-BBB delivered agents within the targeted volume, and the dependence of both on the molecular weight of the delivered compounds have not been extensively investigated. In order to study these characteristics, dextrans at three distinct molecular weights (3, 70, and 2000 kDa) have been employed as model agents. Although compounds larger than 400 Da can be delivered, a size exclusion threshold remains. For example, a 3 kDa dextran has been delivered more diffusely and at a higher concentration than a 70 kDa dextran. Dextrans have also been deposited at larger amounts proximal to larger vessel branches such as the internal and external transverse hippocampal vessels, and the vessels within the thalamus, when compared to other regions in the targeted hippocampus. As a result, although large compounds can be delivered through the BBB, there remain concerns with the effective concentration and spatial distribution of trans-BBB delivered compounds.
FUS-induced BBB opening studies have used microbubble UCA's (e.g., Definity®, SonoVue®, and Optison™) that were either protein- or lipid-shelled with a stabilized gas core. A purpose of these UCA was to provide image contrast while remaining safe for systemic injection by restricting the administered bubble size to below 10 μm. FUS-induced BBB opening, in a stark contrast, involves pre-formed microbubbles to increase the BBB's permeability by opening, for example, the tight junctions or transcellular pathways to allow previously impermeable molecules to go through; in other words, to modulate the biological environment, albeit temporarily. At the low acoustic pressures often used in FUS-induced BBB opening (<1 MPa peak-rarefactional), microbubbles are an important component since opening may not occur without its presence in the vasculature.
Accordingly, there is a need in the art for techniques for opening the BBB in a safe and localized manner.